The major focus of this application is to define the molecular mechanisms of host-parasite interactions as it relates to secondary systemic complications of periodontal disease. We propose to examine the response of defined host cells to the periodontal pathogen Porphyromonas gingivalis. The sequelae associated with periodontal disease have received considerable attention over the past few years. However, little is known about the specific interactions of P. gingivalis with host cells as it relates to cardiovascular disease and diabetes. The goal of this program project is to begin to define the response of host cells to specific P. gingivalis components at the molecular level with particular emphasis on these processes in the context of diabetes, cardiovascular disease, and periodontal disease. Project 1 will examine the molecular mechanisms of P. gingivalis interactions with human endothelial cells by defining the endothelial cell receptor for fimbriae and the signal transduction events concurrent with P. gingivalis infection. Project 2 will examine the role of P. gingivalis fimbriae and LPS in leukocyte recruitment, expression of inflammatory mediators and host-derived proteolytic enzymes, the destruction of hard and soft tissue, and the proliferation of P. gingivalis in vivo. These will be examine din the context of diabetes using 2 well defined animal models. Project 3 will examine the role of the macrophage response to P. gingivalis LPS. The goal of this project will characterize the LPS receptor and Co receptor in normal cells. There are gaps in our knowledge regarding specific details of the interactions between host cells and P. gingivalis particularly in diabetes and cardiovascular disease. This study will use novel approaches to increase our understanding of the molecular mechanisms of host parasite interactions and the modulation of these processes in systemic diseases.